Effect of Body Weight and Age on the Pharmacokinetics of Dihydroartemisinin: Food and Drug Administration Basis for Dose Determination of Artesunate for Injection in Pediatric Patients With Severe Malaria.

For treatment of severe malaria, the World Health Organization recommends 3 mg/kg intravenous artesunate in pediatric patients weighing less than 20 kg. Here we describe the Food and Drug Administration's rationale for selecting 2.4 mg/kg in pediatric patients weighing less than 20 kg based on literature review and independent analyses.

Esomeprazole FDA Approval in Children With GERD: Exposure-Matching and Exposure-Response.

OBJECTIVES: Food and Drug Administration approval of proton-pump inhibitors for infantile gastroesophageal reflux disease has been limited by intrapatient variability in the clinical assessment of gastroesophageal reflux disease. For children 1 to 17 years old, extrapolating efficacy from adults for IV esomeprazole was accepted. The oral formulation was previously approved in children. Exposure-response and exposure matching analyses were sought to identify approvable pediatric doses. METHODS: Intragastric pH biomarker comparisons between children and adults were conducted. Pediatric doses were selected to match exposures in adults and were based on population pharmacokinetic (PK) modeling and simulations with pediatric esomeprazole data. Observed IV or oral esomeprazole PK data were available from 50 and 117 children, between birth and 17 years, respectively, and from 65 adults, between 20 and 48 years. A population PK model developed using these data was used to simulate steady-state esomeprazole exposures for children at different doses to match the observed exposures in adults. RESULTS: Exposure-response relationships of intragastric pH measures were similar between children and adults. The PK simulations identified a dosing regimen for children that results in comparable steady-state area under the curve to that observed after 20 mg in adults. For IV esomeprazole, increasing the infusion duration to 10 to 30 minutes in children achieves matching Cmax values with adults. CONCLUSIONS: The exposure-matching analysis permitted approval of an esomeprazole regimen not studied directly in clinical trials. Exposure-response for intragastric pH-permitted approval for the treatment of gastroesophageal reflux disease in children in whom it was not possible to evaluate the adult primary endpoint, mucosal healing assessed by endoscopy.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy.

Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group.

The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results.

Creating a Roadmap to Quantitative Systems Pharmacology-Informed Rare Disease Drug Development: A Workshop Report.

One of the goals of the Accelerating Rare Disease Cures (ARC) program in the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) is the development and use of regulatory and scientific tools, including drug/disease modeling, dose selection, and translational medicine tools. To facilitate achieving this goal, the FDA in collaboration with the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI) hosted a virtual public workshop on May 11, 2023, entitled "Creating a Roadmap to Quantitative Systems Pharmacology-Informed Rare Disease Drug Development." This workshop engaged scientists from pharmaceutical companies, academic institutes, and the FDA to discuss the potential utility of quantitative systems pharmacology (QSP) in rare disease drug development and identify potential challenges and solutions to facilitate its use. Here, we report the main findings from this workshop, highlight the key takeaways, and propose a roadmap to facilitate the use of QSP in rare disease drug development.

Application of Model-Informed Drug Development in Dose Selection and Optimization for siRNA Therapies.

The application of model-informed drug development (MIDD) has revolutionized drug development and regulatory decision making, transforming the process into one that is more efficient, effective, and patient centered. A critical application of MIDD is to facilitate dose selection and optimization, which play a pivotal role in improving efficacy, safety, and tolerability profiles of a candidate drug. With the surge of interest in small interfering RNA (siRNA) drugs as a promising class of therapeutics, their applications in various disease areas have been extensively studied preclinically. However, dosing selection and optimization experience for siRNA in humans is limited. Unique challenges exist for the dose evaluation of siRNA due to the temporal discordance between pharmacokinetic and pharmacodynamic profiles, as well as limited available clinical experience and considerable interindividual variability. This review highlights the pivotal role of MIDD in facilitating dose selection and optimization for siRNA therapeutics. Based on past experiences with approved siRNA products, MIDD has demonstrated its ability to aid in dose selection for clinical trials and enabling optimal dosing for the general patient population. In addition, MIDD presents an opportunity for dose individualization based on patient characteristics, enhancing the precision and effectiveness of siRNA therapeutics. In conclusion, the integration of MIDD offers substantial advantages in navigating the complex challenges of dose selection and optimization in siRNA drug development, which in turn accelerates the development process, supports regulatory decision making, and ultimately improves the clinical outcomes of siRNA-based therapies, fostering advancements in precision medicine across a diverse range of diseases.

FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma.

In January 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Approval was based on BRUIN, a single-arm study of pirtobrutinib monotherapy in patients with B-cell malignancies. Efficacy was based on independent review committee-assessed overall response rate (ORR) supported by durability of response in 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor and received the approved pirtobrutinib dosage of 200 mg once daily. The ORR was 50% [95% confidence interval (CI), 41-59], and the complete response rate was 13% (95% CI, 7-20), with an estimated median duration of response of 8.3 months. The most common nonhematologic adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Warnings and Precautions in labeling include infection, hemorrhage, cytopenias, atrial arrhythmias, and second primary malignancies. Postmarketing studies were required to evaluate longer-term safety of pirtobrutinib and to verify the clinical benefit of pirtobrutinib. This article summarizes key aspects of the regulatory review, including the indication statement, efficacy and safety considerations, and postmarketing requirements.

Considerations and Challenges in the Remdesivir COVID-19 Pediatric Development Program.

The US Food and Drug Administration is committed to the development of effective antiviral regimens for pediatric patients with coronavirus disease 2019 (COVID-19), including infants and neonates. On April 25, 2022, the approved indication of remdesivir (RDV) was expanded to include pediatric patients 28 days and older and weighing at least 3 kg with positive results of direct severe acute respiratory syndrome coronavirus 2 viral testing, who are: Hospitalized, or Not hospitalized and have mild to moderate COVID-19 and are at high risk for progression to severe COVID-19, including hospitalization or death. Given the similar course of COVID-19 in adults and pediatric patients, the approval of RDV for use in pediatric patients is supported by the safety and efficacy data from adequate and well-controlled phase 3 trials in adults and adolescents; and by the safety and pharmacokinetic data from a single-arm, open-label, phase 2/3 pediatric clinical trial of 53 pediatric patients at least 28 days of age and weighing at least 3 kg with confirmed severe acute respiratory syndrome coronavirus 2 infection and mild, moderate, or severe COVID-19. At the time of the April 25, 2022, approval action, the US Food and Drug Administration also revoked the emergency use authorization for RDV that previously covered this pediatric population. This article summarizes key issues and regulatory considerations involved in the RDV COVID-19 pediatric development program, including the evolution of the emergency use authorization issued for RDV as results from registrational studies became available, and discusses lessons learned.

Model-Informed Approaches to Support Drug Development for Patients With Obesity: A Regulatory Perspective.

Obesity, which is defined as having a body mass index of 30 kg/m2 or greater, has been recognized as a serious health problem that increases the risk of many comorbidities (eg, heart disease, stroke, and diabetes) and mortality. The high prevalence of individuals who are classified as obese calls for additional considerations in clinical trial design. Nevertheless, gaining a comprehensive understanding of how obesity affects the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of drugs proves challenging, primarily as obese patients are seldom selected for enrollment at the early stages of drug development. Over the past decade, model-informed drug development (MIDD) approaches have been increasingly used in drug development programs for obesity and its related diseases as they use and integrate all available sources and knowledge to inform and facilitate clinical drug development. This review summarizes the impact of obesity on PK, PD, and the efficacy of drugs and, more importantly, provides an overview of the use of MIDD approaches in drug development and regulatory decision making for patients with obesity: estimating PK, PD, and efficacy in specific dosing scenarios, optimizing dose regimen, and providing evidence for seeking new indication(s). Recent review cases using MIDD approaches to support dose selection and provide confirmatory evidence for effectiveness for patients with obesity, including pediatric patients, are discussed. These examples demonstrate the promise of MIDD as a valuable tool in supporting clinical trial design during drug development and facilitating regulatory decision-making processes for the benefit of patients with obesity.

Whole Body PBPK Modeling of Remdesivir and Its Metabolites to Aid in Estimating Active Metabolite Exposure in the Lung and Liver in Patients With Organ Dysfunction.

Remdesivir (RDV) is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease 2019 (COVID-19) in certain patients requiring hospitalization. As a nucleoside analogue prodrug, RDV undergoes intracellular multistep activation to form its pharmacologically active species, GS-443902, which is not detectable in the plasma. A question arises that whether the observed plasma exposure of RDV and its metabolites would correlate with or be informative about the exposure of GS-443902 in tissues. A whole body physiologically-based pharmacokinetic (PBPK) modeling and simulation approach was utilized to elucidate the disposition mechanism of RDV and its metabolites in the lungs and liver and explore the relationship between plasma and tissue pharmacokinetics (PK) of RDV and its metabolites in healthy subjects. In addition, the potential alteration of plasma and tissue PK of RDV and its metabolites in patients with organ dysfunction was explored. Our simulation results indicated that intracellular exposure of GS-443902 was decreased in the liver and increased in the lungs in subjects with hepatic impairment relative to the subjects with normal liver function. In subjects with severe renal impairment, the exposure of GS-443902 in the liver was slightly increased, whereas the lung exposure of GS-443902 was not impacted. These predictions along with the organ impairment study results may be used to support decision making regarding the RDV dosage adjustment in these patient subgroups. The modeling exercise illustrated the potential of whole body PBPK modeling to aid in decision making for nucleotide analogue prodrugs, particularly when the active metabolite exposure in the target tissues is not available.

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes.

On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.

Model-Informed Drug Development Approaches to Assist New Drug Development in the COVID-19 Pandemic.

Leveraging limited clinical and nonclinical data through modeling approaches facilitates new drug development and regulatory decision making amid the coronavirus disease 2019 (COVID-19) pandemic. Model-informed drug development (MIDD) is an essential tool to integrate those data and generate evidence to (i) provide support for effectiveness in repurposed or new compounds to combat COVID-19 and dose selection when clinical data are lacking; (ii) assess efficacy under practical situations such as dose reduction to overcome supply issues or emergence of resistant variant strains; (iii) demonstrate applicability of MIDD for full extrapolation to adolescents and sometimes to young pediatric patients; and (iv) evaluate the appropriateness for prolonging a dosing interval to reduce the frequency of hospital visits during the pandemic. Ongoing research activities of MIDD reflect our continuous effort and commitment in bridging knowledge gaps that leads to the availability of effective treatments through innovation. Case examples are presented to illustrate how MIDD has been used in various stages of drug development and has the potential to inform regulatory decision making.

Quantitative systems pharmacology: Landscape analysis of regulatory submissions to the US Food and Drug Administration.

Quantitative systems pharmacology (QSP) has been proposed as a scientific domain that can enable efficient and informative drug development. During the past several years, there has been a notable increase in the number of regulatory submissions that contain QSP, including Investigational New Drug Applications (INDs), New Drug Applications (NDAs), and Biologics License Applications (BLAs) to the US Food and Drug Administration. However, there has been no comprehensive characterization of the nature of these regulatory submissions regarding model details and intended applications. To address this gap, a landscape analysis of all the QSP submissions as of December 2020 was conducted. This report summarizes the (1) yearly trend of submissions, (2) proportion of submissions between INDs and NDAs/BLAs, (3) percentage distribution along the stages of drug development, (4) percentage distribution across various therapeutic areas, and (5) nature of QSP applications. In brief, QSP is increasingly applied to model and simulate both drug effectiveness and safety throughout the drug development process across disease areas.

Anti-SARS-CoV-2 Repurposing Drug Database: Clinical Pharmacology Considerations.

A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti-SARS-CoV-2 Repurposing Drug Database is a database that includes both in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti-SARS-CoV-2 drugs. Continuous development and expansion are feasible with the public availability of this database.

Model-Informed Drug Development in Pediatric Dose Selection.

Model-informed drug development (MIDD) has been a powerful and efficient tool applied widely in pediatric drug development due to its ability to integrate and leverage existing knowledge from different sources to narrow knowledge gaps. The dose selection is the most common MIDD application in regulatory submission related to pediatric drug development. This article aims to give an overview of the 3 broad categories of use of MIDD in pediatric dose selection: leveraging from adults to pediatric patients, leveraging from animals to pediatric patients, and integrating mechanism in infants and neonates. Population pharmacokinetic analyses with allometric scaling can reasonably predict the clearance in pediatric patients aged >5 years. A mechanistic-based approach, such as physiologically based pharmacokinetic accounting for ontogeny, or an allometric model with age-dependent exponent, can be applied to select the dose in pediatric patients aged ≤2 years. The exposure-response relationship from adults or from other drugs in the same class may be useful in aiding the pediatric dose selection and benefit-risk assessment. Increasing application and understanding of use of MIDD have contributed greatly to several policy developments in the pediatric field. With the increasing efforts of MIDD under the Prescription Drug User Fee Act VI, bigger impacts of MIDD approaches in pediatric dose selection can be expected. Due to the complexity of model-based analyses, early engagement between drug developers and regulatory agencies to discuss MIDD issues is highly encouraged, as it is expected to increase the efficiency and reduce the uncertainty.

FDA-Industry Scientific Exchange on assessing quantitative systems pharmacology models in clinical drug development: a meeting report, summary of challenges/gaps, and future perspective.

The pharmaceutical industry is actively applying quantitative systems pharmacology (QSP) to make internal decisions and guide drug development. To facilitate the eventual development of a common framework for assessing the credibility of QSP models for clinical drug development, scientists from US Food and Drug Administration and the pharmaceutical industry organized a full-day virtual Scientific Exchange on July 1, 2020. An assessment form was used to ensure consistency in the evaluation process. Among the cases presented, QSP was applied to various therapeutic areas. Applications mostly focused on phase 2 dose selection. Model transparency, including details on expert knowledge and data used for model development, was identified as a major factor for robust model assessment. The case studies demonstrated some commonalities in the workflow of QSP model development, calibration, and validation but differ in the size, scope, and complexity of QSP models, in the acceptance criteria for model calibration and validation, and in the algorithms/approaches used for creating virtual patient populations. Though efforts are being made to build the credibility of QSP models and the confidence is increasing in applying QSP for internal decisions at the clinical stages of drug development, there are still many challenges facing QSP application to late stage drug development. The QSP community needs a strategic plan that includes the ability and flexibility to Adapt, to establish Common expectations for model Credibility needed to inform drug Labeling and patient care, and to AIM to achieve the goal (ACCLAIM).

A Simulation Approach to Evaluate the Impact of Patterns of Bioanalytical Bias Difference on the Outcome of Pharmacokinetic Similarity Studies.

Pharmacokinetic (PK) similarity studies are vital to assess the biosimilarity of a biosimilar to a reference product. Systematic bias in a bioanalytical method that quantify products could be a potential source of error affecting the variability of the data and influencing the outcome of a PK similarity study. We investigated the impact of six varying patterns of bioanalytical bias difference (biasdiff ) between the similar products on the probability passing the PK similarity test. A population PK model was used to simulate concentration-time profiles for a biosimilar and a reference product and added biasdiff ranging from 030%. The probability of achieving the PK similarity criteria (90% confidence interval between 0.8 and 1.25) for the maximum serum concentration (Cmax ) and area under the curve (AUC) was assessed. The data indicate that an increase in absolute biasdiff between products of ≥ 10% would decrease the power to assess the similarity criteria for Cmax and AUC.

Targeting 11q23 positive acute leukemia cells with high molecular weight-melanoma associated antigen-specific monoclonal antibodies.

BACKGROUND: Acute leukemia with 11q23 aberrations is associated with a poor outcome with therapy. The lack of efficacy of conventional therapy has stimulated interest in developing novel strategies. Recent studies have shown that 11q23-positive acute leukemia cells express the high molecular weight-melanoma associated antigen (HMW-MAA). This tumor antigen represents a useful target to control growth of human melanoma tumors in patients and in severe combined immunodeficient (SCID) mice, utilizing antibody-based immunotherapy. This effect appears to be mediated by inhibition of the HMW-MAA function such as triggering of the focal adhesion kinase/proline-rich tyrosine kinase 2 (Pyk2) pathways. Therefore, in this study we tested whether HMW-MAA-specific monoclonal antibodies (mAb) could inhibit growth of 11q23-positive leukemia cells in SCID mice. METHODS: HMW-MAA-specific mAb were tested for their ability to inhibit the in vitro proliferation of an 11q23-positive acute myeloid leukemia (AML) cell line and blasts from four patients with 11q23 aberrations and their in vivo growth in subcutaneous and disseminated xenograft models. RESULTS: The HMW-MAA-specific mAb did not affect in vitro proliferation although they down-regulated phosphorylated (P) Pyk2 expression. Furthermore, the mAb enhanced the in vitro anti-proliferative effect of cytarabine. In vivo the mAb inhibited the growth of leukemic cells in a dose-dependent fashion. However, the difference did not reach statistical significance. No effect was detected on P-Pyk2 expression. Furthermore, HMW-MAA-specific mAb in combination with cytarabine did not improve tumor inhibition. Lastly, the combination of two mAb which recognize distinct HMW-MAA determinants had no detectable effect on survival in a disseminated xenograft model. CONCLUSIONS: HMW-MAA-specific mAb down-regulated P-Pyk2 expression and enhanced the anti-proliferative effect of cytarabine in vitro, but had no detectable effect on survival or growth of leukemia cells in vivo. Whether the HMW-MAA-specific mAb can be used as carriers of toxins or chemotherapeutic agents against 11q23-acute leukemia remains to be determined.